Cyclic-AMP appears not to be the only modulator of the intracellular response to hormone stimulation in fat cells. A possible role for cyclic GMP and calcium flux at this level can be proposed. Epinephrine induced a very rapid efflux of calcium from fat cells within seconds and a marked increase in cGMP level which reached a peak within 30 sec. The increase of cAMP and the maximal stimulation of the lipolysis occurred at a later time (2-6 min). Theophylline did not stimulate calcium efflux nor had any early effect on cGMP, but stimulated the uptake of calcium, the accumulation of cGMP and cAMP and the rate of lipolysis 2-6 min. Calcium ionophore A 23187 stimulated calcium efflux and cGMP accumulation within seconds, did not affect cAMP but had a short stimulatory effect on lipolysis. Both dibutyryl cGMP and cGMP were able to mimic the effect of A 23187 on lipolysis. Calcium flux and cGMP formation could be the two very early steps of the intracellular response to hormone stimulation and could control the reaction chain that leads to the lipolytic response in fat cells.